抑郁症是高致残性精神疾病，其病因和病理机制尚不清楚，且早期识别与诊治存在诸多挑战。抑郁症众多的临床表现中，快感缺失是重要的核心症状，在伴有忧郁性特征的患者中最为突出。本课题组前期工作及国内外研究表明，抑郁症患者存在奖赏环路异常。奖赏相关核心区域如内侧前额叶-伏隔核-腹侧被盖区与抑郁症的发生发展密切相关，是导致快感缺失的神经环路基础。据此，本研究以奖赏环路为主线，开展抑郁症的病因、诊断与治疗干预研究。计划收集忧郁型抑郁症及其他存在奖赏异常表征的人群，结合影像学、应激评估、遗传学检测及药物干预的方法，明确抑郁症奖赏环路的异常并探讨其对抑郁症早期识别、诊断以及抗抑郁药疗效预测的意义，阐释遗传与环境因素对抑郁症奖赏功能的影响及其生物学基础。同时，通过操控小鼠奖赏环路活动，验证临床研究结果并探讨抑郁症奖赏功能异常的生物学机制。本项目预期将为建立基于奖赏机制的抑郁症客观诊断与治疗优化策略提供全新依据。

Major depressive disorder (MDD) is a highly disabling mental disorder. The etiology and pathogenesis of MDD remains unknown, which cause the under-diagnosis and under-treatment in clinical practice. Among numerous clinical manifestations of MDD, anhedonia is a cardinal symptom of MDD, especially in patients with melancholic features. Our recent work and update studies in the world have shown that patients with MDD exhibit reward circuit dysfunction. The abnormalities of reward-related core areas, such as the prefrontal cortex - nucleus accumbens - ventral tegmental area, are closely associated with the development of MDD, and underlie an important neural basis of anhedonia. Therefore, we design this study, aiming to explore the pathology and mechanisms of diagnose and optimized treatment of patients with MDD. We will enroll patients with MDD, experiencing the melancholic features. The controls are the other diagnosis and with reward dysfunction features. The patients will be follow up for 8 weeks treatment with the antidepressants of different actions. The functional connectivity of reward regions, such as the ventral striatum, nucleus accumbens, and ventral medial prefrontal cortex, will be analyzed to identify the dysfunction of reward circuit of MDD. We will explore the interactive effects of environment stresses and genetic susceptibility on the functioning of reward circuits using the neuroimaging techniques, and to find the objective markers which are helpful for the early diagnose, and prediction of treatment efficacy of antidepressants. Finally, through modulating the reward circuit activity in mice, we will verify and further investigate reward dysfunction of MDD and its biological mechanisms. The project will provide new evidence for the establishment of reward mechanism-based objective diagnosis and optimized treatment of MDD.